title: Hsp90 chaperones PPARγ and regulates differentiation and survival of 3T3-L1 adipocytes.
abstract: Adipose tissue dysregulation has a major role in various human diseases. The peroxisome proliferator-activated receptor-γ (PPARγ) is a key regulator of adipocyte differentiation and function, as well as a target of insulin-sensitizing drugs. The Hsp90 chaperone stabilizes a diverse set of signaling 'client' proteins, thereby regulates various biological processes. Here we report a novel role for Hsp90 in controlling PPARγ stability and cellular differentiation. Specifically, we show that the Hsp90 inhibitors geldanamycin and novobiocin efficiently impede the differentiation of murine 3T3-L1 preadipocytes. Geldanamycin at higher concentrations also inhibits the survival of both developing and mature adipocytes, respectively. Further, Hsp90 inhibition disrupts an Hsp90-PPARγ complex, leads to the destabilization and proteasomal degradation of PPARγ, and inhibits the expression of PPARγ target genes, identifying PPARγ as an Hsp90 client. A similar destabilization of PPARγ and a halt of adipogenesis also occur in response to protein denaturing stresses caused by a single transient heat-shock or proteasome inhibition. Recovery from stress restores PPARγ stability and adipocyte differentiation. Thus, our findings reveal Hsp90 as a critical stress-responsive regulator of adipocyte biology and offer a potential therapeutic target in obesity and the metabolic syndrome.
authors.affiliation: Department of Medical Chemistry, Semmelweis University, Budapest, Hungary.
authors.forename: M T
authors.initials: MT
authors.lastname: Nguyen
authors.forename: P
authors.initials: P
authors.lastname: Csermely
authors.forename: C
authors.identifier: 0000000240577678
authors.initials: C
authors.lastname: Sőti
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D051379:Mice; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D047495:PPAR gamma; D046988:Proteasome Endopeptidase Complex; C001277:geldanamycin